EP0826671B1 - Heterocyclische amidverbindungen und deren medizinische verwendung - Google Patents

Heterocyclische amidverbindungen und deren medizinische verwendung Download PDF

Info

Publication number
EP0826671B1
EP0826671B1 EP96912273A EP96912273A EP0826671B1 EP 0826671 B1 EP0826671 B1 EP 0826671B1 EP 96912273 A EP96912273 A EP 96912273A EP 96912273 A EP96912273 A EP 96912273A EP 0826671 B1 EP0826671 B1 EP 0826671B1
Authority
EP
European Patent Office
Prior art keywords
mmol
give
compound
oxo
title compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP96912273A
Other languages
English (en)
French (fr)
Other versions
EP0826671A1 (de
EP0826671A4 (de
Inventor
Fumihiko-The Green Cross Corp. Cent. Akahoshi
Takuya-The Green Cross Corp. Cent. Yoshimura
Masahiro-The Green Cross Corporation Central EDA
Atsuyuki-The Green Cross Corp. Centr. ASHIMORI
Hajime-The Green Cross Corp. Central Fukuyama
Masahide-The Green Cross Corp. Central NAKAJIMA
Teruaki-The Green Cross Corporation Cent. IMADA
Hideki Okunishi
Mizuo Miyazaki
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tanabe Pharma Corp
Original Assignee
Mitsubishi Pharma Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mitsubishi Pharma Corp filed Critical Mitsubishi Pharma Corp
Publication of EP0826671A1 publication Critical patent/EP0826671A1/de
Publication of EP0826671A4 publication Critical patent/EP0826671A4/de
Application granted granted Critical
Publication of EP0826671B1 publication Critical patent/EP0826671B1/de
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/96—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine

Definitions

  • the present invention relates to novel heterocyclic amide compounds, pharmacologically acceptable salts thereof, pharmaceutical compositions thereof and pharmaceutical use thereof. More particularly, the present invention relates to pyridone- and pyrimidoneacetamide derivatives which are useful pharmacologically, diagnostically and for the prophylaxis and treatment of diseases, and pharmacologically acceptable salts thereof. The present invention also relates to intermediates necessary for the synthesis of the above-mentioned heterocyclic amide compounds.
  • Angiotensin II shows physiological activities such as vasopression by strong contraction of blood vessel, stimulation of aldosterone secretion from adrenal cortex (aldosterone retains sodium), and the like, and is considered to be a causative substance or risk factor of diseases such as hypertension, hypercardia, myocardial infarction, arteriosclerosis, diabetic and non-diabetic renal diseases, vascular restenosis after PTCA (percutaneous transluminal coronary angioplasty) and the like.
  • diseases such as hypertension, hypercardia, myocardial infarction, arteriosclerosis, diabetic and non-diabetic renal diseases, vascular restenosis after PTCA (percutaneous transluminal coronary angioplasty) and the like.
  • angiotensin II is generated by cleavage of two amino acid residues from angiotensin I, which is a peptide consisting of ten amino acids present in a living body, and that angiotensin converting enzyme (ACE) is involved in said cleavage.
  • ACE angiotensin converting enzyme
  • chymase is known to use, as substrates, numerous physiologically active substances such as extracellular matrix, cytokine, substance P, VIP (vasoactive intestinal polypeptide), apoprotein B and the like, and known to be responsible for the activation of other proteases such as collagenase ( Igakuno Ayumi , Miyazaki et al., 1995, 172, p. 559).
  • physiologically active substances such as extracellular matrix, cytokine, substance P, VIP (vasoactive intestinal polypeptide), apoprotein B and the like, and known to be responsible for the activation of other proteases such as collagenase ( Igakuno Ayumi , Miyazaki et al., 1995, 172, p. 559).
  • chymase inhibitors are expected to become inhibitors of angiotensin II action, as well as agents for the prophylaxis and treatment of various diseases caused by chymase, since it inhibits generation of ACE non-dependent angiotensin II.
  • a patent application drawn to a chymase inhibitor based on these ideas has been already filed (WO93/25574).
  • Patent applications filed by ZENECA LTD. Japanese Patent Unexamined Publication Nos. 5-286946, 6-56785 and WO93/21210
  • J. Med. Chem. 1994, 37, p. 3090 J. Med. Chem. 1994, 37, p. 3303
  • J. Med. Chem. 1994, 37, p 3313 and others disclose or report heterocyclic compounds which are human leukocyte elastase inhibitors, and these compounds are known to selectively inhibit human leukocyte elastase.
  • EP-A-0 509 769 describes certain heterocyclic amides, which are 1-pyridylacetamide compounds of formula I, as defined, which are inhibitors of human leukocyte elastase (HLE). Furthermore, EP-A-0 509 769 discloses intermediates useful in the synthesis of those heterocyclic amides, processes for preparing the heterocyclic amides, pharmaceutical compositions containing such heterocyclic amides and methods for their use.
  • EP-A-0 528 633 relates to certain substituted heterocycles, which are 1-pyrimidinylacetamide compounds of formula I, as defined, which are inhibitors of HLE. EP-A-0 528 633 also describes intermediates useful in the synthesis of those substituted heterocycle, processes for preparing the substituted heterocycles, pharmaceutical compositions containing such substituted heterocycles and methods for their use.
  • WO-A-93/21209 certain heterocyclic ketones, which are 1-pyridylacetamide ketones of formula I, as defined, which are inhibitors of HLE, are disclosed.
  • WO-A-93/21209 relates to intermediates useful in the synthesis of those heterocyclic ketones, processes for preparing the heterocyclic ketones, pharmaceutical compositions containing such heterocyclic ketones and methods for their use.
  • WO-A-93/21210 relates to certain substituted ketones, which are 1-pyrimidinylacetamide derivatives of formula I, as defined, which are inhibitors of HLE. WO-A-93/21210 also describes intermediates useful in the synthesis of those substituted ketones, processes for preparing the substituted ketones, pharmaceutical compositions containing such substituted ketones and methods for their use.
  • WO-A-93/21212 describes certain heterocyclic compounds, which are 1-pyridylacetamide compounds of formula (I), as defined, which are inhibitors of HLE, as well as intermediates useful in the synthesis of those heterocyclic compounds, processes for preparing the heterocyclic compounds, pharmaceutical compositions containing such heterocyclic compounds and methods for their use.
  • WO-A-95/26958 discloses compounds (N-(pyrimidinyl)-aspartic acid ⁇ -substituted methyl ketones and aspartic acid aldehydes), compositions and methods for inhibiting interleukin-1 ⁇ (IL- ⁇ ) protease activity.
  • the present inventors have conducted intensive studies in an attempt to achieve the above-mentioned objects, and found that, by modifying or converting a part of the structure of the compound disclosed by ZENECA LTD., compounds can be obtained that inhibit chymase group, inclusive of human heart chymase, with high selectivity, without inhibiting other enzymes such as human leukocyte elastase, and exhibit superior absorption and safety, which resulted in the completion of the present invention.
  • the present invention relates to heterocyclic amide compounds of the formula (I) wherein
  • the present invention also relates to the above-mentioned heterocyclic amide compounds wherein, in the formula (I), Y is aryl optionally having substituent(s), and pharmacologically acceptable salts thereof; the above-mentioned heterocyclic amide compounds wherein, in the formula (I), Z is -CF 2 R 8 or -CF 2 CONR 9 R 10 , and pharmacologically acceptable salts thereof; and the above-mentioned heterocyclic amide compounds wherein, in the formula (I), one of R 5 , R 6 and R 7 is aryl optionally having substituent(s) and the rest are hydrogen, provided that when M is nitrogen, R 6 is void, and pharmacologically acceptable salts thereof.
  • the present invention relates to the heterocyclic amide compound 2-[5-methylamino-2-(4-dimethylaminophenyl)-6-oxo-1,6-dihydro-1-pyrimidyl]-N-(1-benzyl-3,3,3-trifluoro-2-oxopropyl)-acetamide, or a pharmacologically acceptable salt thereof.
  • the present invention further relates to compounds of the formula (II) which are useful for synthesizing compound (I) wherein each symbol is as defined above (hereinafter this compound is also referred to as compound (II)).
  • the present invention also relates to pharmaceutical compositions containing compound (I) or a pharmacologically acceptable salt thereof and a pharmacologically acceptable carrier, and to pharmaceutical use thereof, particularly to chymase inhibitors.
  • Alkyl at R 1 , R 11 and R 2 -R 10 may be straight or branched and has 1 to 6 carbon atoms, and is exemplified by methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, and n-hexyl.
  • Cycloalkyl at R 1 , R 11 , R 9 , R 10 and Y has 3 to 7 carbon atoms, and is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • Cycloalkylalkyl at R 1 , R 11 , R 9 and R 10 has the same cycloalkyl moiety as above and its alkyl moiety may be straight or branched and has 1 to 3 carbon atoms. Examples thereof include cyclopropylmethyl, 2-cyclobutylethyl, 3-cyclopentylpropyl, cyclohexylmethyl, 2-cyclohexylethyl, and cycloheptylmethyl.
  • Aryl at R 1 , R 11 , R 5 -R 10 and Y is phenyl, naphthyl, or an ortho-fused bicyclic group having 8 to 10 cyclic atoms wherein at least one ring is aromatic ring (e.g., indenyl).
  • Arylalkyl at R 1 , R 11 and R 2 -R 10 has the same aryl moiety as above and its alkyl moiety may be straight or branched and has 1 to 3 carbon atoms. Examples thereof include benzyl, phenethyl, 3-phenylpropyl, 1-naphthylmethyl, 2-naphthylmethyl, 2-(1-naphthyl)ethyl, 2-(2-naphthyl)ethyl, 3-(1-naphthyl)propyl, and 3-(2-naphthyl)propyl.
  • Arylalkenyl at R 5 -R 7 has the same aryl moiety as above and its alkenyl moiety may be straight or branched and has 2 to 6 carbon atoms. Examples thereof include 3-phenyl-2-propenyl, 4-phenyl-3-butenyl, 5-phenyl-4-pentenyl, 6-phenyl-5-hexenyl, 3-(1-naphthyl)-2-propenyl, and 4-(2-naphthyl)-3-butenyl.
  • Arylalkenyl at R 8 -R 10 has the same aryl moiety as above and its alkenyl moiety may be straight or branched and has 3 to 6 carbon atoms. Examples thereof include 3-phenyl-2-propenyl, and 4-phenyl-3-butenyl.
  • Heteroaryl at R 1 , R 11 , R 5 -R 10 and Y is a 5 or 6-membered ring having carbon atom(s) and 1 to 4 hetero atoms (oxygen, sulfur or nitrogen) and an ortho-fused bicyclic heteroaryl having 8 to 10 cyclic atoms, particularly benzo derivatives, and those produced by fusing propenylene, trimethylene or tetramethylene therewith, and its stable N-oxide.
  • Examples thereof include pyrrolyl, furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, tetrazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl, isobenzofuranyl, chromenyl, isoindolyl, indolyl, indazolyl, isoquinolyl
  • Heteroarylalkyl at R 1 , R 11 and R 5 -R 10 has the same heteroaryl moiety as above and its alkyl moiety may be straight or branched and has 1 to 3 carbon atoms.
  • Examples thereof include 2-pyrrolylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-thienylmethyl, 2-(2-pyridyl)ethyl, 2-(3-pyridyl)ethyl, 2-(4-pyridyl) ethyl, and 3-(2-pyrrolyl)propyl.
  • Heteroarylalkenyl at R 5 -R 7 has the same heteroaryl moiety as above and its alkenyl moiety may be straight or branched and has 2 to 6 carbon atoms. Examples thereof include 3-(2-pyridyl)-2-propenyl, 4-(3-pyridyl)-3-butenyl, 5-(2-pyrrolyl)-4-pentenyl, and 6-(2-thienyl)-5-hexenyl.
  • Heteroarylalkenyl at R 8 -R 10 has the same heteroaryl moiety as above and its alkenyl moiety may be straight or branched and has 3 to 6 carbon atoms. Examples thereof include 3-(2-pyridyl)-2-propenyl, and 4-(2-pyridyl)-3-butenyl.
  • Heterocycle at R 1 and R 11 is a 4 to 6-membered ring having carbon atom(s) and 1 to 4 hetero atoms (oxygen, sulfur or nitrogen), which is exemplified by azetidinyl, pyrrolidinyl, piperidinyl, piperidino, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, oxothiomorpholinyl, dioxothiomorpholinyl, tetrahydropyranyl, and dioxacyclohexyl.
  • Heterocycle represented by -NR 3 R 4 and -NR 9 R 10 is a 4 to 6-membered ring having carbon atom(s), at least one nitrogen atom and optionally other hetero atom (oxygen or sulfur), which is exemplified by azetidinyl, pyrrolidinyl, piperidino, piperazinyl, morpholino, thiomorpholino, oxothiomorpholino, and dioxothiomorpholino.
  • Heterocyclealkyl at R 1 , R 11 , R 9 and R 10 has the same heterocycle moiety as above (R 1 , R 11 ) and its alkyl moiety may be straight or branched and has 1 to 3 carbon atoms.
  • Examples thereof include azetidinylethyl, pyrrolidinylpropyl, piperidinylmethyl, piperidinoethyl, piperazinylethyl, morpholinylpropyl, morpholinomethyl, thiomorpholinylethyl, oxothiomorpholinylethyl, dioxothiomorpholinylethyl, tetrahydropyranylpropyl, and dioxacyclohexylmethyl.
  • Halogen at R 8 is exemplified by fluorine, chlorine, bromine and iodine.
  • Perfluoroalkyl at R 8 may be straight or branched and has 1 to 6 carbon atoms. Examples thereof include trifluoromethyl, pentafluoroethyl, and heptafluoropropyl.
  • Aminoalkyl at R 8 has an alkyl moiety which may be straight or branched and has 1 to 6 carbon atoms. Examples thereof include aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl, and aminohexyl.
  • Alkylaminoalkyl at R 8 has an alkyl moiety which may be straight or branched and has 1 to 6 carbon atoms. Examples thereof include methylaminomethyl, methylaminoethyl, ethylaminopropyl, ethylaminobutyl, methylaminopentyl, and methylaminohexyl.
  • Dialkylaminoalkyl at R 8 has an alkyl moiety which may be straight or branched and has 1 to 6 carbon atoms. Examples thereof include dimethylaminomethyl, dimethylaminoethyl, diethylaminopropyl, diethylaminobutyl, dimethylaminopentyl, and dimethylaminohexyl.
  • Alkoxyalkyl at R 8 has an alkoxy moiety and alkyl moiety which may be respectively straight or branched and have 1 to 6 carbon atoms. Examples thereof include methoxymethyl, methoxyethyl, ethoxypropyl, ethoxybutyl, methoxypentyl, and methoxyhexyl.
  • Hydroxyalkyl at R 8 has an alkyl moiety which may be straight or branched and has 1 to 6 carbon atoms. Examples thereof include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, and hydroxyhexyl.
  • Alkenyl at R 9 and R 10 may be straight or branched and has 3 to 6 carbon atoms, and is exemplified by 2-propenyl, 3-butenyl, 4-pentenyl, and 5-hexenyl.
  • alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heterocycle and heterocyclealkyl may be substituted by one or more substituents seleted from halogen, hydroxy, nitro, cyano, trifluoromethyl, alkyl, alkoxy, alkylthio, formyl, acyloxy, oxo, phenyl, arylalkyl, -COORa, -CH 2 COORa, -OCH 2 COORa, -CONRbRc, -CH 2 CONRbRc, -OCH 2 CONRbRc, -COO(CH 2 ) 2 NReRf, -SO 2 T 1 , -CONRdSO 2 T 1 , -NReRf, -NRgCHO,
  • Alkoxy may be straight or branched and as 1 to 6 carbon atoms. Examples thereof include methoxy, ethoxy, propoxy, butoxy, pentyloxy, and hexyloxy
  • Alkylthio may be straight or branched and has 1 to 6 carbon atoms. Examples thereof include methylthio, ethylthio, propylthio, butylthio, pentylthio, and hexylthio.
  • Acyloxy may be straight or branched and has 1 to 6 carbon atoms. Examples thereof include formyloxy, acetyloxy, propionyloxy, butyryloxy, valeryloxy, pivaloyloxy, and hexanoyloxy.
  • Ra-Rn means hydrogen, alkyl (as defined above) or arylalkyl (as defined above).
  • T 1 -T 4 mean the same groups as the above-mentioned R 1 , which may be substituted by the above-mentioned substituents.
  • the compound (I) can exist as optically active compounds and racemates due to asymmetric carbon to which -(CH 2 )n-Y is bonded. Said racemates can be resolved into optically active compounds by a me hod known per se .
  • the compound can exist as diastereomer mixtures or a single diastereomer. Each diastereomer can be isolated by a method known per se .
  • the compound (I) can exhibit a polymorphism, and can exist as more than one tautomers. In addition, it can exist as solvates (e.g., ketone solvate, and hydrate).
  • the present invention encompasses any stereoisomers, optical isomers, polymorphs, tautomers, solvates mentioned above and optional mixtures thereof.
  • the compound (I) is an acidic compound
  • its pharmacologically acceptable salt is exemplified by an alkali metal salt (e.g., salts with lithium, sodium, and potassium), alkaline earth metal salt (e.g., salts with calcium, and magnesium), aluminum salt, ammonium salt, and salts with an organic base (e.g., salts with triethylamine, morpholine, piperidine, and triethanolamine).
  • the compound (I) is a basic compound
  • its pharmacologically acceptable salt is exemplified by an inorganic acid addition salt (e.g., salts with hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, and phosphoric acid), organic acid addition salt (e.g., salts with methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, citric acid, malonic acid, fumaric acid, glutaric acid, adipic acid, maleic acid, tartaric acid, succinic acid, mandelic acid, and malic acid), and salts with an amino acid (e.g., salts with glutamic acid, and aspartic acid).
  • an inorganic acid addition salt e.g., salts with hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric
  • preferable compound is a compound wherein, in the formula (I), Y is aryl optionally having substituent(s); a compound wherein, in the formula (I), Z is -CF 2 R 8 or -CF 2 CONR 9 R 10 ; and a compound wherein, in the formula (I), one of R 5 , R 6 and R 7 is aryl optionally having substituent(s) and the rest are hydrogen, provided that when M is nitrogen, R 6 is void.
  • More preferable compound is exemplified by the compounds of Examples to be mentioned later, namely, compounds of Examples 3, 4, 7, 8, 29, 33, 48, 50, 61, 62, 83, 84, 87, 88, 90 and 93.
  • R 11 is hydroxy-protecting group (e.g., tert-butyldimethylsilyl, triisopropylsilyl, and tert-butyldiphenylsilyl), cbz is benzyloxycarbonyl and other symbols are as defined above.
  • R 11 is hydroxy-protecting group (e.g., tert-butyldimethylsilyl, triisopropylsilyl, and tert-butyldiphenylsilyl)
  • cbz is benzyloxycarbonyl and other symbols are as defined above.
  • compound (III) is condensed with amine A to give compound (VII) or compound (III) is condensed with amine A' to give compound (IV).
  • the compound (III) may be a compound disclosed in publications (e.g., Japanese Patent Unexamined Publication Nos. 6-56785, 5-286946, Warner et al., J. Med. Chem. 1994, 37, p. 3090, umblewood et al., J. Med. Chem. 1994, 37, p. 3303, and Veale et al., J. Med. Chem. 1995, 38, p. 98, WO93/21210) or can be prepared by a conventional method based on these publications. The production methods of amine A and amine A' are described later.
  • a condensing agent used for this condensation and which activates carboxylic acid of compound (III) may be suitably dicyclohexylcarbodiimide (DCC)/hydroxybenzotriazole (HOBT), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (WSCI), hydrochloride thereof/HOBT, WSCI or hydrochrolide thereof/4-dimethylaminopyridine (DMAP), 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), carbonyldiimidazole (CDI)/HOBT, and diethylphosphoryl cyanide.
  • DCC dicyclohexylcarbodiimide
  • HBT hydroxybenzotriazole
  • WSCI N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide
  • DMAP 2-ethoxy-1-ethoxycarbonyl-1,2-dihydr
  • Said reaction is generally carried out in an inert solvent wherein the inert solvent used may be any as long as it is aprotic. Suitable examples thereof include acetonitrile, dichloromethane, chloroform, and N,N-dimethylformamide.
  • the condensation is generally carried out at a temperature of -30°C to 80°C, preferably 0°C to 25°C.
  • Benzyloxycarbonyl of compound (IV) can be removed by a conventional method, such as hydrogenolysis, to give compound (V).
  • the amino bound to carbon on heterocyclic ring (e.g., pyridone ring or pyrimidone ring) of compound (V) is acylated or sulfonylated by a conventional method to give a compound (VI) wherein R is substituent other than hydrogen.
  • a compound (VI) wherein R is -CHO, -CONH 2 , -COR 1 , -COOR 1 , -CONHOR 1 , -CONHR 1 , -CONR 1 R 11 , -CONHSO 2 R 1 , -COSR 1 , -COCOR 2 , -COCOOR 2 , -CONHCOOR 2 or -COCONR 3 R 4 is synthesized by using an active carboxylic acid derivative such as acid halide, using carboxylic acid and a coupling agent, and other method.
  • the method therefor includes the use of activated thiocarboxylic acid derivative (e.g., thioyl chloride, and lower alkyl ester of dithioic acid), or the use of thioic acid and a coupling agent.
  • activated thiocarboxylic acid derivative e.g., thioyl chloride, and lower alkyl ester of dithioic acid
  • thioic acid and a coupling agent e.g., thioyl chloride, and lower alkyl ester of dithioic acid
  • a method may be used wherein dimethyl trithiocarbonate is used with an alcohol of the formula: R 1 OH, thiol of the formula: R 1 SH or amine of the formula: R 1 NH 2 .
  • isothiocyanate may be used.
  • an organic base e.g., triethylamine, or pyridine
  • inorganic base e.g., sodium carbonate, or potassium carbonate
  • compound (VI) comprises -COORa (carboxyl) wherein Ra is hydrogen as a substituent of each substituent at R or Z
  • said compound is obtained by decomposing the corresponding ester (compound (VI) having, as substituent of substituent, -COORa wherein Ra is not hydrogen) synthesized using a suitably-removable acid protecting group.
  • This decomposition can be carried out by a various methods known in organic chemistry, such as basic hydrolysis using lithium hydroxide or sodium hydroxide or hydrogenolysis of benzyl ester.
  • compound (VI) comprises -COORa, -CONRbRc, -COO(CH 2 ) 2 NReRf or -CONRdSO 2 T 1 as a substituent of each substituent at R or Z
  • said compound is obtained by reacting a compound of the formula: HORa, HNRbRc, HO(CH 2 ) 2 NReRf or HNRdSO 2 T 1 (when Ra-Rf is not hydrogen), and compound (VI) having, as substituent of substituent, -COORa (carboxyl) wherein Ra is hydrogen, or its active derivative.
  • compound (VI) comprises -OCH 2 COORa or -OCH 2 CONRbRc as a substituent of each substituent at R 5 -R 7 , R or Z, for example, said compound is obtained by reacting a compound of the formula: BrCH 2 COORa, ICH 2 COORa, BrCH 2 CONRbRc or ICH 2 CONRbRc (when Ra-Rc is not hydrogen) and compound (VI) having, as substituent of substituent, hydroxy in the presence of a base such as sodium hydride.
  • a base such as sodium hydride
  • compound (VI) comprises -NRgCOT 2 , -NRgCOOT 2 , -NRhCQNRiRj, -NRkSO 2 T 3 or acyloxy as a substituent of each substituent at R 5 -R 7 , R or Z, for example, said compound is obtained by reacting the corresponding compound (VI) having, as substituent of substituent, hydroxy or amino such as -NHRg, -NHRh or -NHRk, with an active derivative of an acid of the formula: HOCOT 2 , HOCOOT 2 , HOCQNRiRj or HOSO 2 T 3 .
  • compound (VI) comprises heteroaryl-N-oxide in R 5 -R 7 , R or Z
  • said compound is obtained by oxidizing the corresponding compound (VI) having heteroaryl in R 5 -R 7 , R or Z using a conventional oxidizing agent such as dioxirane in acetone.
  • the compound (II) is obtained by removing the hydroxy-protecting group (R 11 ) of compound (VI). This compound (II) is useful as an intermediate for the synthesis of compound (I).
  • the hydroxy-protecting group is removed using tetrabutylammonium fluoride in an inert solvent such as tetrahydrofuran, wherein the reaction mixture is preferably bufferred using an acid such as acetic acid.
  • the oxidization is preferably carried out by, for example, using dimethyl sulfoxide in excess and water soluble carbodiimide at about room temperature in an inert solvent such as toluene and using dichloroacetic acid as a catalyst.
  • Other useful methods include, for example, the use of aqueous alkaline potassium permanganate solution; the use of oxalyl chloride, dimethyl sulfoxide and tertiary amine; the use of acetic anhydride and dimethyl sulfoxide; the use of pyridine-sulfur trioxide complex and dimethyl sulfoxide; the use of chromium (VI) oxide-pyridine complex in methylene chloride; and the use of hypervalent iodine reagent such as periodinane (e.g., 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one) in dichloromethane or dimethylformamide.
  • This compound may be subjected to acylation to give compound (I) wherein R is other than hydrogen.
  • Scheme II shows different production method of compound (IV). This method is applicable only when M is carbon. wherein each symbol is as defined above.
  • compound (VIII) compound disclosed in publications such as Japanese Patent Unexamined Publication No. 6-56785, Warner et al., J. Med. Chem. 1994, 37, p. 3090 and umblewood et al., J. Med. Chem. 1994, 37, p. 3303, or compound prepared by a conventional method according to these publications
  • compound B is reacted to give compound (IV).
  • the production method of compound B is described below.
  • This reaction includes, for example, as disclosed in Japanese Patent Unexamined Publication No. 6-56785 and J. Med. Chem. 1994, 37, p. 3303, treating compound (VIII) in an aprotic solvent, particularly an inert solvent such as N,N-dimethylformamide and tetrahydrofuran, using a base, such as sodium hydride and potassium hydride, at -30°C to 80°C, preferably at 0°C to 30°C and then reacting the resulting compound with compound B at -30°C to 80°C, preferably at 0°C to 30°C.
  • an aprotic solvent particularly an inert solvent such as N,N-dimethylformamide and tetrahydrofuran
  • a base such as sodium hydride and potassium hydride
  • Amine A, amine A' and compound B necessary for the above-mentioned synthesis can be synthesized by the methods shown in the following schemes III-VII.
  • N-aroylamino acid derivative (IX) is treated with acetic anhydride to give oxazolone (X).
  • This oxazolone (X) is reacted with acid anhydride (e.g., when Z is CF 3 , it is trifluoroacetic anhydride) having the desired Z to give compound (XI) into which acyl has been introduced.
  • amine A can be synthesized wherein Z is -CF 2 R 8 wherein R 8 is not limited to hydrogen, fluorine, alkyl and perfluoroalkyl. wherein each symbol is as defined above.
  • a suitable nitroalkane (XIV) is condensed with compound (XV) to give nitro alcohol (XVI).
  • the compound (XV) can be synthesized by, for example, the method disclosed in the report of Welch (Tetrahedron Lett. 1987, 43, p. 3123) combined with general methods in organic chemistry.
  • compound (XV) can exist as hydrate or hemiacetal. Then, according to the method of, for example, Abeles et al. (Biochemistry, 1987, 26, p. 4474), nitro of this compound (XVI) is reduced with a suitable reducing agent to give amine A.
  • R 8 is a substituent having amino and hydroxy, said amino and hydroxy need to be protected by a stable protecting group in each reaction mentioned above.
  • Scheme V shows synthetic method of amine A wherein Z is -COOR 9 .
  • Rp is amino-protecting group (e.g., benzyloxycarbonyl (cbz), tert-butoxycarbonyl (BOC) and the like), Rq is alkyl having 1 to 6 carbon atoms and other symbols are as defined above.
  • This esterification may be carried out by, for example, reacting the compound with alkyl halide corresponding to Rq, in the presence of a base such as potassium hydrogencarbonate, or by reacting with diazoalkane.
  • ⁇ -amino acids of the formula (XVII) wherein amino is protected are commercially available, when using one which is not commercially available, such ⁇ -amino acid can be synthesized by obtaining amino acid from aldehyde Y-(CH 2 )nCHO by Strecker synthesis method or other method known per se , followed by protection of the amino.
  • compound (XVIII) is reduced using, for example, diisobutyl-aluminum hydride to give compound (XX) with ease.
  • compound (XVII) is condensed with N,O-dimethylhydroxylamine to give an amide derivative and the derivative is reduced with lithium aluminum hydride for the desired synthesis.
  • a different method include reducing compound (XVIII) with, for example, sodium borohydride/lithium chloride to give compound (XIX) and oxidizing compound (XIX) by the oxidizing method, which has been described for conversion of compound (II) to compound (I), to give compound (XX).
  • compound (XX) treated with cyanide salt, preferably potassium cyanide or sodium cyanide, in the presence of an auxiliary solvent such as tetrahydrofuran, ethyl acetate and dioxane in an aqueous solution to give compound (XXI).
  • cyanide salt preferably potassium cyanide or sodium cyanide
  • the compound (XXI) thus obtained can be converted to amine A wherein Z is -COOR 9 by decomposition of cyano by the addition of alcohol.
  • This reaction is generally done by reacting compound (XXI) and compound R 9 OH in the presence of a suitable proton source (e.g., hydrogen chloride).
  • a suitable proton source e.g., hydrogen chloride
  • the protecting group Rp of amino may be simultaneously removed.
  • the protecting group is eliminated by a method known per se .
  • amine A is synthesized as in the following.
  • a different method includes reacting amine A wherein Z is -COOR 9 with excess amine HNR 9 R 10 in a lower alcohol, preferably methanol, ethanol or isopropanol, at 25 - 100°C. In this case, a reaction in a closed system using a stainless steel autoclave is preferable.
  • R 9 and R 10 are substituents having amino are as described above.
  • Scheme VI shows synthetic method of amine A wherein Z is -CF 2 COOR 9 or -CF 2 CONR 9 R 10 . wherein each symbol is as defined above.
  • compound (XX) synthesized in scheme V is reacted with (1) ethyl bromodifluoroacetate in the presence of zinc powder according to the method of Hallinan and Fried (Tetrahedron Lett. 1984, 25, p. 2301) and Thairivongs et al. (J. Med. Chem. 1986, 29, p. 2080); or (2) ethyl chlorodifluoroacetate in the presence of zinc powder according to the method of Lang and Schaub (Tetrahedron Lett. 1988, 29, p. 2943); or (3) ethyl bromodifluoroacetate, zinc powder and titanium tetrachloride according to the method of Hoover (US Patent No. 4,855,303) to give compound (XXII) wherein Z is -CF 2 COOCH 2 CH 3 .
  • amine A wherein Z is -CF 2 CONR 9 R 10 or -CF 2 COOR 9 can be synthesized from compound (XXII) wherein Z is -CF 2 COOCH 2 CH 3 by the following method.
  • amine A can be obtained as mentioned above, hydroxy of this amine A is protected by a hydroxy-protecting group (R 11 ) to give amine A'.
  • the hydroxy-protecting group is to be introduced when amino is protected by a protecting group Rp, and thereafter, amino-protecting group is removed.
  • Scheme VII shows synthetic method of compound B. wherein each symbol is as defined above.
  • this compound B is synthesized according to the report of Damewood et al. (J. Med. Chem. 1994, 37, p. 3303), wherein amine A is reacted with chloroacetyl chloride in an inert solvent such as tetrahydrofuran in the presence of an organic base such as N-methylmorpholine, at -20°C to 60°C, preferably at 0°C to 30°C, to give compound (XXV), whose hydroxy is protected by the above-mentioned protecting group (R 11 ), of which preferred is silyl such as tert-butyldimethylsilyl, to give compound (XXVI).
  • This compound is reacted with sodium iodide or potassium iodide in an inert solvent such as acetone at -20°C to 60°C, preferably at 0°C to 30°C, to give the desired compound B.
  • the compound (I) of the present invention thus produced can be recovered at optional purity by known methods for separation and purification, such as concentration, extraction, chromatography, reprecipitation, recrystallization and the like.
  • the pharmacologically acceptable salts of said compound (I) can be also produced by a known method. Further, various isomers of said compound (I) can be produced by a known method.
  • the compound (I) and pharmacologically acceptable salts thereof of the present invention have superior inhibitory action on chymase groups in mammals such as humans, dogs, and cats.
  • the compound (I) and pharmacologically acceptable salts thereof of the present invention are useful as inhibitors of chymase groups inclusive of human heart chymase and are useful for the prophylaxis and treatment of various diseases caused by chymase, namely, for the prophylaxis and treatment of diseases considered to be caused by angiotensin II (e.g., hypertension, hypercardia, myocardial infarction, arteriosclerosis, diabetic and non-diabetic renal diseases, vascular restenosis after PTCA).
  • angiotensin II e.g., hypertension, hypercardia, myocardial infarction, arteriosclerosis, diabetic and non-diabetic renal diseases, vascular restenosis after PTCA.
  • pharmacologically acceptable carriers are used to prepare pharmaceutical composition in the form of granules, tablets, capsules, injection, ointments, creams, and aerosols which can be administered orally or parenterally.
  • the above-mentioned pharmaceutical preparation contains an effective amount of compound (I) or its pharmacologically acceptable salt.
  • the dose of said compound (I) and its pharmacologically acceptable salt varies depending on administration route, symptoms of patients, body weight and age, and appropriately determined according to the administration purposes. In general, 0.01-1000 mg/kg body weight/day, preferably 0.05-500 mg/kg body weight/day, thereof is administered orally to an adult in a single to several doses per day.
  • 1 H-NMR was determined at 200, 300 or 500 MHz.
  • the chemical shift of 1 H-NMR is expressed in parts per million (ppm) of relative delta ( ⁇ ) values using tetramethylsilane (TMS) as an internal standard.
  • the coupling constant is expressed by s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets), brs (broad singlet), ABq (AB quartet) and the like, while indicating obvious multiplicity by hertz (Hz).
  • Thin layer and column chromatographies were performed using a silica gel manufactured by Merck. For concentration, a rotary evaporator manufactured by Tokyo Rikakikai Co., Ltd. was used.
  • Example 2 To a mixed solution of the title compound in Example 1 (734 mg, 1.27 mmol) in ethanol (20 mL) and THF (20 mL) was added 1N hydrochloric acid (0.2 mL), and 10% palladium carbon (270 mg) was added under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 6 h under a hydrogen atmosphere. Palladium carbon was removed by filtration and washed with ethanol. The filtrate was concentrated, and the residue obtained was separated and purified by silica gel column chromatography (chloroform-methanol, 91: 9) to give 466 mg (83%) of the title compound as pale-yellow crystals.
  • Example 3 The title compound was synthesized in the same manner as in Example 2. That is, the title compound in Example 3 (705 mg, 1.18 mmol) was reacted under a hydrogen atmosphere in the presence of 10% palladium carbon in a mixed solvent of ethanol (20 mL), THF (20 mL) and 1N hydrochloric acid (0.2 mL) to give 217 mg (40%) of the title compound as pale-yellow crystals.
  • Example 5 To a mixed solution of the title compound in Example 5 (500 mg, 0.844 mmol) in methanol (20 mL) and formic acid (1.0 mL) was added 10% palladium carbon (199 mg) under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 14 h. Palladium carbon was removed by filtration and washed with ethanol. The filtrate was concentrated, added to saturated aqueous sodium hydrogencarbonate solution (50 mL), and then extracted with ethyl acetate. The extract was washed with saturated brine and the solvent was evaporated under reduced pressure.
  • Example 7 The title compound was synthesized in the same manner as in Example 2. That is, the title compound in Example 7 (1.28 g, 2.16 mmol) was reacted under a hydrogen atmosphere in the presence of 10% palladium carbon (460 mg) in a mixed solution of ethanol (20 mL), THF (20 mL) and 1N hydrochloric acid (0.4 mL) to give 330 mg (33%) of the title compound as pale-yellow crystals.
  • Example 9 To a mixed solution of the title compound in Example 9 (150 mg, 0.210 mmol) in THF (5 ml) and methanol (3 ml) was added 10% palladium carbon (60 mg) and formic acid (0.3 mL) under a nitrogen atmosphere. The resulting mixture was stirred for 48 h. The catalyst was removed by filtration and washed with THF. The residue obtained by concentration of the filtrate was separated and purified by silica gel column chromatography (chloroform-methanol, 90:10), and further by preparative TLC (chloroform-methanol, 90:10) to give 20.0 mg (16%) of the title compound as a pale-yellow solid.
  • Example 11 The title compound was synthesized in the same manner as in Example 2. That is, the title compound in Example 11 (78.6 mg, 0.133 mmol) was reacted under a hydrogen atmosphere in the presence of 10% palladium carbon (22.9 mg) in a mixed solution of 1,4-dioxane (2 mL) and 1N hydrochloric acid (0.4 mL) to give 39.0 mg (64%) of the title compound as a pale-yellow solid.
  • Example 13 The title compound was synthesized in the same manner as in Example 2. That is, the title compound in Example 13 (79.5 mg, 0.138 mmol) was reacted under a hydrogen atmosphere in the presence of 10% palladium carbon (20 mg) in ethanol (5 mL) to give 40 mg (65%) of the title compound as pale-brown crystals.
  • Example 15 The title compound was synthesized in the same manner as in Reference Example 2. That is, the title compound in Example 15 (878 mg, 1.52 mmol) was reacted under a hydrogen atmosphere in the presence of 10% palladium carbon (323 mg) in a mixed solution of ethanol (25 mL) and 1N hydrochloric acid (0.2 mL) to give 451 mg (67%) of the title compound as colorless crystals.
  • Example 17 The title compound was synthesized in the same manner as in Example 2. That is, the title compound in Example 17 (620 mg, 1.24 mmol) was reacted under a hydrogen atmosphere in the presence of 10% palladium carbon (386 mg) in a mixed solvent of ethanol (25 mL) and 1N hydrochloric acid (0.2 mL) to give 181 mg (40%) of the title compound as colorless crystals.
  • Example 19 The title compound was synthesized in the same manner as in Example 6. That is, the title compound in Example 19 (385 mg, 0.766 mmol) was treated with formic acid (0.3 mL) and 10% palladium carbon (165 mg) in methanol (6 mL) to give 100 mg (35%) of the title compound as colorless crystals.
  • Example 21 The title compound was synthesized in the same manner as in Example 6. That is, the title compound in Example 21 (1.42 g, 2.75 mmol) was treated with formic acid (1.0 mL) and 10% palladium carbon (583 mg) in methanol (20 mL) to give 435 mg (41%) of the title compound as colorless crystals.
  • Example 23 The title compound was synthesized in the same manner as in Example 6. That is, the title compound in Example 23 (742 mg, 1.25 mmol) was treated with formic acid (0.4 mL) and 10% palladium carbon (271 mg) in methanol (8 mL) to give 410 mg (72%) of the title compound as a colorless amorphous.
  • Example 25 To a solution of the title compound in Example 25 (561 mg, 0.915 mmol) and anisole (0.32 mL, 2.9 mmol) in dichloromethane (12 mL) was added trifluoromethanesulfonic acid (0.50 mL, 5.7 mmol) under ice-cooling. The resulting mixture was stirred at 0°C-room temperature for 1 h. Saturated aqueous sodium hydrogencarbonate solution (12 mL) was added under ice-cooling. After stirring for 30 min, the reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution (50 mL), and then extracted with ethyl acetate.
  • Example 27 The title compound was synthesized in the same manner as in Example 26. That is, the title compound in Example 27 (497 mg, 0.817 mmol) was treated with anisole (0.28 mL, 2.6 mmol) and trifluoromethanesulfonic acid (0.43 mL, 4.9 mmol) in dichloromethane (10 mL) to give 377 mg (97%) of the title compound as colorless crystals.
  • Example 28 To a solution of the title compound in Example 28 (375 mg, 0.790 mmol) in dichloromethane (10 mL) was added a solution of boron tribromide in dichloromethane (1.0 M, 16 mL, 16 mmol). The resulting mixture was stirred at room temperature for 24 h, and methanol (3 mL) was added. After stirring for 10 min, the reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution (50 mL), and then extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • Example 30 The title compound was synthesized in the same manner as in Example 26. That is, the title compound in Example 30 (587 mg, 0.941 mmol) was treated with anisole (0.33 mL, 3.0 mmol) and trifluoromethanesulfonic acid (0.55 mL, 6.2 mmol) in dichloromethane (10 mL) to give 287 mg (62%) of the title compound as pale-brown crystals.
  • Example 30 To a mixture of the title compound in Example 30 (2.00 g, 3.21 mmol), THF (30 mL) and water (13 mL) were added iron powder (2.15 g, 38.5 mmol) and 1N hydrochloric acid (1.7 mL). The resulting mixture was stirred at room temperature for 18 h. The reaction mixture was filtrated through Celite and insolubles were washed with ethyl acetate. The filtrate was poured into saturated aqueous sodium hydrogencarbonate solution (150 mL), and then extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate.
  • Example 30 The title compound was synthesized in the same manner as in Example 2.
  • the title compound in Example 30 (196 mg, 0.314 mmol) was reacted under a hydrogen atmosphere in the presence of 10% palladium carbon (100 mg) in a mixed solution of acetic acid (3 mL) and perchloric acid (70%, 3 drops) to give 68 mg (44%) of the title compound as pale-yellow powdery crystals.
  • Example 32 To a mixed solution of the title compound in Example 32 (235 mg, 0.396 mmol) in methanol (10 mL) and formalin (2 mL) was added 10% palladium carbon (89 mg) under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1.5 h under a hydrogen atmosphere. Palladium carbon was removed by filtration and washed with methanol. The filtrate was concentrated and the residue was separated and purified by silica gel column chromatography (dichloromethane-ethyl acetate, 75:25) to give 135 mg (55%) of the title compound as colorless crystals. Recrystallization thereof from chloroform-hexane (50:50) gave 56 mg of colorless crystals.
  • Example 34 The title compound was synthesized in the same manner as in Example 26.
  • the title compound in Example 34 (53 mg, 0.085 mmol) was treated with anisole (0.03 mL, 0.3 mmol) and trifluoromethanesulfonic acid (0.05 mL, 0.6 mmol) in dichloromethane (3 mL) to give 36 mg (87%) of the title compound as colorless crystals.
  • Example 34 To a solution of the title compound in Example 34 (90 mg, 0.148 mmol) in a mixed solution of methanol (4 mL) and formic acid (0.2 mL) was added 10% palladium carbon (31 mg) under a nitrogen atmosphere. The resulting mixture was stirred for 16 h under a hydrogen atmosphere. Palladium carbon was removed by filtration and washed with methanol. The filtrate was concentrated, poured into saturated aqueous sodium hydrogencarbonate solution (50 mL), and then extracted with ethyl acetate. The extract was washed with saturated brine and the solvent was evaporated under reduced pressure.
  • Example 32 To a solution of the title compound in Example 32 (310 mg, 0.522 mmol) in THF (8 mL) was added sodium carbonate (220 mg, 2.08 mmol), and after cooling with ice, acetyl chloride (0.07 mL, 1 mmol) was added. The resulting mixture was stirred at 0°C for 1 h, poured into 1N hydrochloric acid (40 mL), and then extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution (40 mL) and saturated brine, and dried over anhydrous magnesium sulfate.
  • Example 37 The title compound was synthesized in the same manner as in Example 6. That is, the title compound in Example 37 (107 mg, 0.168 mmol) was treated with formic acid (0.25 mL) and 10% palladium carbon (38 mg) in methanol (5 mL) to give 39 mg (46%) of the title compound as a pale-yellow solid.
  • Example 32 To a solution of the title compound in Example 32 (300 mg, 0.505 mmol) and triethylamine (0.09 mL, 0.6 mmol) in THF (10 mL) was added trifluoromethanesulfonyl anhydride (0.10 mL, 0.59 mmol) at -78°C. The resulting mixture was stirred at -78°C for 1.5 h, and water (2 mL) was added. After stirring at room temperature for 30 min, the reaction mixture was poured into water (50 mL), and then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure.
  • Example 39 The title compound was synthesized in the same manner as in Example 26.
  • the title compound in Example 39 (100 mg, 0.138 mmol) was treated with anisole (0.05 mL, 0.5 mmol) and trifluoromethanesulfonic acid (0.075 mL, 0.85 mmol) in dichloromethane (8 mL) to give 77 mg (94%) of the title compound as colorless crystals.
  • Example 32 The title compound was synthesized in the same manner as in Example 37.
  • the title compound in Example 32 (300 mg, 0.505 mmol) was reacted with isopropyl chloroformate (0.12 mL, 1.1 mmol) in the presence of sodium carbonate (106 mg, 1.00 mmol) in THF (8 mL) to give 320 mg (93%) of the title compound as colorless crystals.
  • Example 41 The title compound was synthesized in the same manner as in Example 2. That is, the title compound in Example 41 (88 mg, 0.13 mmol) was reacted under a hydrogen atmosphere in the presence of 10% palladium carbon (29 mg) in methanol (5 mL) to give 52 mg (73%) of the title compound as pale-yellow crystals.
  • Example 43 The title compound was synthesized in the same manner as in Example 26.
  • the title compound in Example 43 (405 mg, 0.606 mmol) was treated with anisole (0.21 mL, 1.9 mmol) and trifluoromethanesulfonic acid (0.29 mL, 3.3 mmol) in dichloromethane (7 mL) to give 305 mg (94%) of the title compound as yellow crystals.
  • Example 43 The title compound was synthesized in the same manner as in Example 32. That is, the title compound in Example 43 (887 mg, 1.33 mmol) was treated with iron powder (890 mg, 15.9 mmol) and 1N hydrochloric acid (0.7 mL) in a mixed solution of THF (13 mL) and water (6 mL) to give 788 mg (97%) of the title compound as pale-yellow crystals.
  • Example 45 The title compound was synthesized in the same manner as in Example 2.
  • the title compound in Example 45 (150 mg, 0.246 mmol) was reacted under a hydrogen atmosphere in the presence of 10% palladium carbon (56 mg) in a mixed solution of methanol (5 mL) and THF (3 mL) to give 104 mg (89%) of the title compound as pale-brown crystals.
  • Example 47 The title compound was synthesized in the same manner as in Example 2. That is, the title compound in Example 47 (200 mg, 0.345 mmol) was reacted under a hydrogen atmosphere in the presence of 10% palladium carbon (144 mg) in a mixed solution of methanol (6 mL) and THF (4 mL) to give 111 mg (72%) of the title compound as a colorless solid.
  • Example 49 The title compound was synthesized in the same manner as in Example 2.
  • the title compound in Example 49 (250 mg, 0.431 mmol) was treated under a hydrogen atmosphere in the presence of 10% palladium carbon (114 mg) in a mixed solution of methanol (6 mL) and THF (4 mL) to give 161 mg (84%) of the title compound as a pale-yellow solid.
  • Example 51 The title compound was synthesized in the same manner as in Example 26. That is, the title compound in Example 51 (760 mg, 1.30 mmol) was treated with anisole (0.45 mL, 4.1 mmol) and trifluoromethanesulfonic acid (0.70 mL, 7.9 mmol) in dichloromethane (15 mL) to give 415 mg (71%) of the title compound as pale-yellow crystals.
  • Example 2 To a solution of the title compound in Example 2 (200 mg, 0.452 mmol) in THF (10 mL) were added sodium carbonate (128 mg, 1.21 mmol) and isopropyl chlorocarbonate (68.8 ⁇ L, 0.605 mmol). The resulting mixture was stirred at room temperature for 17 h. Ethyl acetate (70 mL) was added and the mixture was washed with saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (chloroform-methanol, 19:1) to give 167 mg (66%) of the title compound as colorless crystals.
  • Example 5 The title compound was synthesized in the same manner as in Example 55. That is, the title compound in Example 2 (600 mg, 1.36 mmol) was reacted with sodium carbonate (400 mg, 3.77 mmol) and methyloxalyl chloride (167 ⁇ L, 1.76 mmol) in THF (30 mL) to give 467 mg (65%) of the title compound as pale-yellow crystals.
  • Example 5 The title compound was synthesized in the same manner as in Example 55. That is, the title compound in Example 2 (600 mg, 1.36 mmol) was reacted with sodium carbonate (400 mg, 3.77 mmol) and methylmalonyl chloride (189 ⁇ L, 1.76 mmol) in THF (30 mL) to give 293 mg (40%) of the title compound as pale-yellow crystals.
  • Example 5 The title compound was synthesized in the same manner as in Example 55. That is, the title compound in Example 2 (600 mg, 1.36 mmol) was reacted with sodium carbonate (400 mg, 3.77 mmol) and methylsuccinyl chloride (217 ⁇ L, 1.76 mmol) in THF (30 mL) to give 576 mg (76%) of the title compound as colorless crystals.
  • Example 5 The title compound was synthesized in the same manner as in Example 55. That is, the title compound in Example 2 (900 mg, 2.03 mmol) was reacted with sodium carbonate (600 mg, 5.66 mmol) and methylglutaryl chloride (364 ⁇ L, 2.63 mmol) to give 762 mg (66%) of the title compound as a colorless solid.
  • Example 56 To a solution of the title compound in Example 56 (350 mg, 0.660 mmol) in THF (20 mL) was added 0.1N aqueous sodium hydroxide solution (6.60 mL). The resulting mixture was stirred at room temperature for 2 h. 1N Hydrochloric acid (0.726 mL) was added and the mixture was concentrated under reduced pressure. The resulting suspension was extracted with ethyl acetate. The extract was washed with saturated brine and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Recrystallization from ethyl acetate-hexane (1:5) gave 313 mg (92%) of the title compound as pale-yellow crystals.
  • Example 57 The title compound was synthesized in the same manner as in Example 60. That is, the title compound in Example 57 (280 mg, 0.514 mmol) was reacted with 0.1M aqueous sodium hydroxide solution (5.14 mL) in THF (15 mL) to give 251 mg (92%) of the title compound as pale-yellow crystals.
  • Example 60 The title compound was synthesized in the same manner as in Example 60. That is, the title compound in Example 58 (360 mg, 0.645 mmol) was treated with 0.1N aqueous sodium hydroxide solution (6.45 mL) in THF (15 mL) to give 311 mg (88%) of the title compound as colorless crystals.
  • Example 5 The title compound was synthesized in the same manner as in Example 55. That is, the title compound in Example 2 (300 mg, 0.678 mmol) was reacted with sodium carbonate (200 mg, 1.89 mmol) and benzoyl chloride (106 ⁇ L, 0.908 mmol) in THF (15 mL) to give 271 mg (73%) of the title compound as colorless crystals.
  • Example 5 The title compound was synthesized in the same manner as in Example 55. That is, the title compound in Example 2 (300 mg, 0.678 mmol) was reacted with sodium carbonate (200 mg, 1.89 mmol) and phenylacetyl chloride (120 ⁇ L, 0.908 mmol) in THF (30 mL) to give 188 mg (50%) of the title compound as colorless crystals.
  • Example 5 The title compound was synthesized in the same manner as in Example 55. That is, the title compound in Example 2 (300 mg, 0.678 mmol) was treated with sodium carbonate (200 mg, 1.89 mmol) and cinnamoyl chloride (151 mg, 0.908 mmol) in THF (30 mL) to give 176 mg (45%) of the title compound as pale-yellow crystals.
  • Example 2 To a solution of the title compound in Example 2 (400 mg, 0.900 mmol) in THF (30 mL) were added pyridine (362 ⁇ L, 4.50 mmol) and benzenesulfonyl chloride (138 ⁇ L, 1.08 mmol) under ice-cooling. The resulting mixture was stirred at room temperature for 7 h. Benzenesulfonyl chloride (69.0 ⁇ L, 0.540 mmol) was added and the resulting mixture was stirred at room temperature for 17 h. Benzenesulfonyl chloride (69.0 ⁇ L, 0.540 mmol) was further added, and the mixture was stirred at room temperature for 8 h.
  • Example 66 The title compound was synthesized in the same manner as in Example 66. That is, the title compound in Example 2 (400 mg, 0.900 mmol) was reacted with pyridine (362 ⁇ L, 4.50 mmol) and p-toluenesulfonyl chloride (412 mg, 2.16 mmol) in THF (30 mL) to give 399 mg (74%) of the title compound as a colorless powder.
  • Example 66 The title compound was synthesized in the same manner as in Example 66. That is, the title compound in Example 2 (400 mg, 0.900 mmol) was reacted with pyridine (362 ⁇ L, 4.50 mmol) and methanesulfonyl chloride (140 ⁇ L, 1.80 mmol) in THF (30 mL) to give 307 mg (65%) of the title compound as a colorless powder.
  • Example 2 To a solution of the title compound in Example 2 (400 mg, 0.900 mmol) in THF (30 mL) were added pyridine (362 ⁇ L, 4.50 mmol) and 4-(chlorosulfonyl)benzoic acid (298 mg, 1.35 mmol) under ice-cooling. The resulting mixture was stirred at room temperature for 16 h. Saturated aqueous potassium dihydrogenphosphate solution (20 mL) and ethyl acetate (30 mL) were added. The aqueous layer was separated and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate.
  • pyridine 362 ⁇ L, 4.50 mmol
  • 4-(chlorosulfonyl)benzoic acid 298 mg, 1.35 mmol
  • Example 70 To a solution of the title compound in Example 70 (110 mg, 0.173 mmol) in THF (1 mL) was added an aqueous solution (0.3 mL) of lithium hydroxide (18.2 mg, 0.433 mmol). The resulting mixture was stirred at room temperature overnight. 1N Hydrochloric acid was added adjust the mixture to pH 3, and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), and the mixture was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • Example 72 The title compound was synthesized in the same manner as in Example 71. That is, the title compound in Example 72 (65.9 mg, 0.104 mmol) was treated with an aqueous solution (0.3 mL) of lithium hydroxide (4.79 mg, 0.114 mmol) in THF (1 mL) to give 13 mg (20%) of the title compound as pale-yellow crystals.
  • Example 74 The title compound was synthesized in the same manner as in Example 71. That is, the title compound in Example 74 (150 mg, 0.268 mmol) was treated with an aqueous solution (0.5 mL) of lithium hydroxide (25.2 mg, 0.600 mmol) in THF (2 mL) to give 30 mg (21%) of the title compound as colorless crystals.
  • Example 76 The title compound was synthesized in the same manner as in Example 71. That is, the title compound in Example 76 (150 mg, 0.268 mmol) was treated with an aqueous solution (0.5 mL) of lithium hydroxide (25.2 mg, 0.600 mmol) in THF (2 mL) to give 50 mg (34%) of the title compound as colorless crystals.
  • Example 55 The title compound was synthesized in the same manner as in Example 55. That is, the title compound in Example 2 (559 mg, 1.26 mmol) was reacted with sodium carbonate (372 mg, 3.51 mmol) and acetyl chloride (0.10 mL, 1.4 mmol) in THF (10 mL) to give 509 mg (83%) of the title compound as colorless crystals.
  • Example 5 The title compound was synthesized in the same manner as in Example 55. That is, the title compound in Example 4 (600 mg, 1.30 mmol) was reacted with sodium carbonate (384 mg, 3.62 mmol) and methylsuccinyl chloride (0.18 mL, 1.5 mmol) in THF (12 mL) to give 736 mg (98%) of the title compound as a colorless amorphous.
  • Example 79 The title compound was synthesized in the same manner as in Example 60. That is, the title compound in Example 79 (347 mg, 0.602 mmol) was reacted with 0.1N aqueous sodium hydroxide solution (10 mL) in THF (10 mL) to give 295 mg (87%) of the title compound as colorless crystals.
  • Example 8 The title compound was synthesized in the same manner as in Example 55. That is, the title compound in Example 8 (350 mg, 0.763 mmol) was reacted with sodium carbonate (226 mg, 2.13 mmol) and methylsuccinyl chloride (0.11 mL, 0.89 mmol) in THF (8 mL) to give 250 mg (57%) of the title compound as a colorless amorphous.
  • Example 81 The title compound was synthesized in the same manner as in Example 60. That is, the title compound in Example 81 (203 mg, 0.355 mmol) was reacted with 0.1N aqueous sodium hydroxide solution (5 mL) in THF (5 mL) to give the title compound (quant.) as a colorless amorphous.
  • Example 94 The title compound was synthesized in the same manner as in Example 60. That is, the title compound in Example 94 (200 mg, 0.309 mmol) was reacted with 0.1N aqueous sodium hydroxide solution (4 mL) in THF (4 mL) to give 171 mg (89%) of the title compound as colorless crystals.
  • Example 94 The title compound was synthesized in the same manner as in Example 2. That is, the title compound in Example 94 (930 mg, 1.44 mmol) was reacted under a hydrogen atmosphere in the presence of 10% palladium carbon (306 mg) in methanol (10 mL) to give 682 mg (92 %) of the title compound as colorless crystals.
  • Example 96 The title compound was synthesized in the same manner as in Example 60. That is, the title compound in Example 96 (90.2 mg, 0.176 mmol) was reacted with 0.1 N aqueous sodium hydroxide solution (2.5 mL) in THF (2.5 mL) to give 71 mg (83%) of the title compound as colorless crystals.
  • Example 96 The title compound was synthesized in the same manner as in Example 55. That is, the title compound in Example 96 (470 mg, 0.917 mmol) was reacted with sodium carbonate (272 mg, 2.57 mmol) and methylsuccinyl chloride (0.14 mL, 1.1 mmol) in THF (10 mL) to give 548 mg (95%) of the title compound as a colorless amorphous.
  • Example 98 The title compound was synthesized in the same manner as in Example 60. That is, the title compound in Example 98 (265 mg, 0.423 mmol) was reacted with 0.1N aqueous sodium hydroxide solution (10 mL) in THF (10 mL) to give 208 mg (84%) of the title compound as colorless crystals.
  • the effectiveness of the inhibitory activity of compound (I) of the present invention was evaluated based on the inhibitory activity on amidase activity of human heart chymase, which was determined as in the following.
  • the inhibitory activity was quantitatively determined through variation in fractional residual activity of the enzyme caused by the inventive compound in defined serial concentration ( ⁇ 1, ⁇ 10, ⁇ 100-fold equivalents) relative to 5 nM chymase in the presence of synthetic substrate, succinyl-alanyl-alanyl-prolyl-phenylalanine-p-nitroanilide (final concentration 2.5 mM).
  • the inhibitory effect was analyzed by least square regression of Easson-Stedman plot (Proc. Roy. Soc. B. 1936, 121, p. 141) utilizing bimolecular equilibrium reaction linearization formula.
  • the inhibitory activity was evaluated by the apparent inhibitory constant (Kiapp) obtained by this analysis and inhibitory constant (Ki) calculated from final substrate concentration in the reaction mixture and Km values separately determined.
  • the quantitative determination of initial rate of the enzyme reaction was spectrophotometrically detected in terms of an increased amount of p-nitroaniline at 405 nm produced by hydrolysis of the substrate.
  • the chymase inhibitory activity of the compound of the present invention was calculated as ratio of residual activity in the presence of inhibitor relative to enzyme activity in the absence of inhibitor, and incorporation of the determination values was completed at a level less than initial rate guarantee absorbance at a concentration of the substrate used for the enzyme, after which analysis was performed.
  • the reaction mixture consisted of an Na 2 B 4 O 7 (100 mM)-KH 2 PO 4 (50 mM) buffer (pH 9.0, 120 ⁇ l) containing 0.1% TritonTM-X100, the inventive compound dissolved in 20 ⁇ l of 10% dimethyl sulfoxide (DMSO), 10% bovine serum albumin dissolved in 20 ⁇ l of the same buffer, substrate dissolved in 20 ⁇ l of DMSO, and 20 ⁇ l of chymase, thus amounting to 200 ⁇ l in total.
  • DMSO dimethyl sulfoxide
  • bovine serum albumin dissolved in 20 ⁇ l of the same buffer
  • substrate dissolved in 20 ⁇ l of DMSO
  • 20 ⁇ l of chymase thus amounting to 200 ⁇ l in total.
  • reaction rates of the control and the sample added with the inhibitor were calculated for certain time period ( ⁇ 20 min) with successive shift (every 10 to 30 minutes) of the period, and the residual activity ratio was quantitatively determined and analyzed from the respective reaction rates averaged through the entire reaction time.
  • the inhibitory activity against human leukocyte elastase was determined using N-methoxysuccinyl-alanyl-alanyl-prolyl-valine-p-nitroanilide as a substrate and 0.1 M Tris-HCl (pH 8.0) containing 20 mM CaCl 2 and 0.1% TweenTM 80 as a buffer, wherein other compositions and method were the same as above.
  • the inhibitory activity against human leukocyte elastase was >10 5 ⁇ M for every compound.
  • the compound (I) of the present invention does not inhibit human leukocyte elastase at all, but strongly inhibits human heart chymase.
  • compound (I) of the invention 10 mg
  • fine particle No. 209 for direct compression 106.6 mg
  • magnesium aluminate metasilicate 20% corn starch 30% lactose 50%
  • crystalline cellulose 24.0 mg
  • calcium carboxylmethylcellulose 4.0 mg
  • magnesium stearate 0.4 mg
  • (1), (3) and (4) were respectively passed through a 100 mesh sieve in advance. These (1), (3), (4) and (2) were respectively dried to certain water contents, and mixed in a mixer at the above-mentioned weight ratios. To the entirely homogeneous powder mixture was added (5) and the mixture was mixed for a short time (30 sec). The mixed powder was compressed using a pounder (6.3 mm ⁇ , 6.0 mm R) to give tablets weighing 85 mg per tablet.
  • These tablets may be coated using an enteric film coating agent such as polyvinylacetal diethylaminoacetate) or edible colorant, as necessary.
  • enteric film coating agent such as polyvinylacetal diethylaminoacetate
  • the above-mentioned ingredients were weighed and homogeneously mixed.
  • the mixed powder was filled in hard gelatin capsules by 200 mg each.
  • hydrochloride of compound (I) of the invention 5 mg (2) sucrose 100 mg (3) physiological saline 10 ml
  • the mixed solution of the above ingredients was passed through a membrane filter, and again sterilized by filtration.
  • the filtered solution was aseptically dispensed into vials, and the vials were sealed after filling nitrogen gas, to give intravenous injections.
  • heterocyclic amide compounds and pharmacologically acceptable salts thereof of the present invention have superior inhibitory activity against chymase groups in mammals inclusive of human, and can be administered orally or parenterally. Therefore, they are useful as chymase inhibitors and can be effective for the prophylaxis and treatment of various diseases caused by chymase, such as those caused by angiotensin II.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Claims (8)

  1. Heterocyclische Amidverbindung der Formel (I) wobei
    R Wasserstoff, -CHO, -CONH2, -COR1, -COOR1, -CONHOR1, -CONHR1, -CONR1R1', -CONHSO2R1, -COSR1, -COCOR2, -COCOOR2, -CONHCOOR2, -COCONR3R4, -CSXR1, -SO2WR1, -SO2NR1R1' oder -SO2E ist,
    wobei
    R1 und R1' gleich oder verschieden sein können und jeweils unabhängig voneinander Alkyl, Cycloalkyl, Cycloalkylalkyl, Aryl, Arylalkyl, Heteroaryl, Heteroarylalkyl, Heterocyclyl oder Heterocyclylalkyl sind,
    R2, R3 und R4 gleich oder verschieden sein können und jeweils unabhängig voneinander Wasserstoff, Alkyl oder Arylalkyl sind,
    -NR3R4 zu Heterocyclyl kombiniert sein kann,
    X eine direkte Bindung, -NH-, -O- oder -S- ist,
    W eine direkte Bindung, -NH-, -NHCO-, -NHCOO- oder -NHCONH- ist, und
    E Hydroxy oder Amino ist;
    R5, R6 und R7 gleich oder verschieden sein können und jeweils unabhängig voneinander Wasserstoff oder Alkyl sind, oder eines von R5, R6 und R7 Aryl, Arylalkyl, Arylalkenyl, Heteroaryl, Heteroarylalkyl oder Heteroarylalkenyl ist und die übrigen Wasserstoff sind;
    M ein Kohlenstoff oder ein Stickstoff ist, mit der Maßgabe, dass, wenn M ein Stickstoff ist, R6 nicht vorhanden ist;
    Y Cycloalkyl, Aryl oder Heteroaryl ist;
    Z -CF2R8, -CF2CONR9R10, -CF2COOR9, -COOR9 oder -CONR9R10 ist,
    wobei
    R8 Wasserstoff, Halogen, Alkyl, Perfluoralkyl, Aminoalkyl, Alkylaminoalkyl, Dialkylaminoalkyl, Alkoxyalkyl, Hydroxyalkyl, Aryl, Arylalkyl, Arylalkenyl, Heteroaryl, Heteroarylalkyl oder Heteroarylalkenyl ist,
    R9 und R10 gleich oder verschieden sein können und jeweils unabhängig voneinander Wasserstoff, Alkyl, Alkenyl, Cycloalkyl, Cycloalkylalkyl, Heterocyclylalkyl, Aryl, Arylalkyl, Arylalkenyl, Heteroaryl, Heteroarylalkyl oder Heteroarylalkenyl sind, und - NR9R10 zu Heterocyclyl kombiniert sein kann; und
    n 0 oder 1 ist;
    mit der Maßgabe, dass die vorstehend genannten Reste Alkyl, Cycloalkyl, Cycloalkylalkyl, Aryl, Arylalkyl, Arylalkenyl, Heteroaryl, Heteroarylalkyl, Heteroarylalkenyl, Heterocyclyl und Heterocyclylalkyl gegebenenfalls Substituenten aufweisen, oder
    ein pharmakologisch verträgliches Salz davon,
    wobei
    Alkyl an R1, R1' und R2 bis R10 geradkettig oder verzweigt sein kann und 1 bis 6 Kohlenstoffatome aufweist,
    Cycloalkyl an R1, R1', R9, R10 und Y 3 bis 7 Kohlenstoffatome aufweist,
    Cycloalkylalkyl an R1, R1', R9 und R10 die gleiche Cycloalkyleinheit wie vorstehend aufweist und seine Alkyleinheit geradkettig oder verzweigt sein kann und 1 bis 3 Kohlenstoffatome aufweist,
    Aryl an R1, R1', R5 bis R10 und Y Phenyl, Naphthyl oder ein ortho-anellierter bicyclischer Rest mit 8 bis 10 Atomen im Cyclus ist, wobei mindestens ein Ring ein aromatischer Ring ist,
    Arylalkyl an R1, R1' und R2 bis R10 die gleiche Aryleinheit wie vorstehend aufweist und seine Alkyleinheit geradkettig oder verzweigt sein kann und 1 bis 3 Kohlenstoffatome aufweist,
    Arylalkenyl an R5 bis R7 die gleiche Aryleinheit wie vorstehend aufweist und seine Alkenyleinheit geradkettig oder verzweigt sein kann und 2 bis 6 Kohlenstoffatome aufweist,
    Arylalkenyl an R8 bis R10 die gleiche Aryleinheit wie vorstehend aufweist und seine Alkenyleinheit geradkettig oder verzweigt sein kann und 3 bis 6 Kohlenstoffatome aufweist,
    Heteroaryl an R1, R1', R5 bis R10 und Y ein 5- oder 6-gliedriger Ring mit Kohlenstoffatom(en) und 1 bis 4 Heteroatomen und ein ortho-anelliertes bicyclisches Heteroaryl mit 8 bis 10 Atomen im Ring ist,
    Heteroarylalkyl an R1, R1' und R5 bis R10 die gleiche Heteroaryleinheit wie vorstehend aufweist und seine Alkyleinheit geradkettig oder verzweigt sein kann und 1 bis 3 Kohlenstoffatome aufweist,
    Heteroarylalkenyl an R5 bis R7 die gleiche Heteroaryleinheit wie vorstehend aufweist und seine Alkenyleinheit geradkettig oder verzweigt sein kann und 2 bis 6 Kohlenstoffatome aufweist,
    Heteroarylalkenyl an R8 bis R10 die gleiche Heteroaryleinheit wie vorstehend aufweist und seine Alkenyleinheit geradkettig oder verzweigt sein kann und 3 bis 6 Kohlenstoffatome aufweist,
    Heterocyclyl an R1 und R1' ein 4- bis 6-gliedriger Ring mit Kohlenstoffatom(en) und 1 bis 4 Heteroatomen (Sauerstoff, Schwefel oder Stickstoff) ist,
    Heterocyclyl, das durch -NR3R4 und -NR9R10 dargestellt ist, ein 4- bis 6-gliedriger Ring mit Kohlenstoffatom(en), mindestens einem Stickstoffatom und gegebenenfalls einem anderen Heteroatom ist,
    Heterocyclylalkyl an R1, R1', R9 und R10 die gleiche Heterocyclyleinheit wie vorstehend (R1, R1') aufweist und seine Alkyleinheit geradkettig oder verzweigt sein kann und 1 bis 3 Kohlenstoffatome aufweist,
    Perfluoralkyl an R8 geradkettig oder verzweigt sein kann und 1 bis 6 Kohlenstoffatome aufweist,
    Aminoalkyl an R8 eine Alkyleinheit aufweist, die geradkettig oder verzweigt sein kann und 1 bis 6 Kohlenstoffatome aufweist,
    Alkylaminoalkyl an R8 eine Alkyleinheit aufweist, die geradkettig oder verzweigt sein kann und 1 bis 6 Kohlenstoffatome aufweist,
    Dialkylaminoalkyl an R8 eine Alkyleinheit aufweist, die geradkettig oder verzweigt sein kann und 1 bis 6 Kohlenstoffatome aufweist,
    Alkoxyalkyl an R8 eine Alkoxyeinheit und eine Alkyleinheit aufweist, die jeweils geradkettig oder verzweigt sein können und 1 bis 6 Kohlenstoffatome aufweisen,
    Hydroxyalkyl an R8 eine Alkyleinheit aufweist, die geradkettig oder verzweigt sein kann und 1 bis 6 Kohlenstoffatome aufweist,
    Alkenyl an R9 und R10 geradkettig oder verzweigt sein kann und 3 bis 6 Kohlenstoffatome aufweist, und
    die vorstehend genannten Substituenten Alkyl, Cycloalkyl, Cycloalkylalkyl, Aryl, Arylalkyl, Arylalkenyl, Heteroaryl, Heteroarylalkyl, Heteroarylalkenyl, Heterocyclyl und Heterocyclylalkyl mit einem oder mehreren Substituenten substituiert sein können, ausgewählt aus Halogen, Hydroxy, Nitro, Cyano, Trifluormethyl, Alkyl, Alkoxy, Alkylthio, Formyl, Acyloxy, Oxo, Phenyl, Arylalkyl, -COORa, -CH2COORa, -OCH2COORa, -CONRbRc, -CH2CONRbRc, -OCH2CONRbRc, -COO(CH2)2NReRf, -SO2T1, -CONRdSO2T1, -NReRf, -NRgCHO, -NRgCOT2, -NRgCOOT2, -NRhCQNRiRj, -NRkSO2T3, -SO2NRlRm und -SO2NRnCOT4, wobei Alkoxy geradkettig oder verzweigt sein kann und 1 bis 6 Kohlenstoffatome aufweist, Alkylthio geradkettig oder verzweigt sein kann und 1 bis 6 Kohlenstoffatome aufweist, Acyloxy geradkettig oder verzweigt sein kann und 1 bis 6 Kohlenstoffatome aufweist, Ra-Rn Wasserstoff, Alkyl (wie vorstehend definiert) oder Arylalkyl (wie vorstehend definiert) bedeutet;
    -NRbRc, -NReRf, -NRiRj und -NRlRm zusammen mit dem benachbarten Stickstoff Heterocyclyl bedeuten (die gleichen wie diejenigen, die durch -NR3R4 und -NR9R10 beispielhaft dargestellt wurden und die mit den vorstehend genannten Substituenten substituiert sein können) und
    - NReRf Heteroaryl mit =O bedeutet,
    T1-T4 die gleichen Gruppen wie das vorstehend erwähnte R1 bedeuten, die mit den vorstehend erwähnten Substituenten substituiert sein können, und
    Q=O oder =S bedeutet.
  2. Heterocyclische Amidverbindung gemäß Anspruch 1, wobei in der Formel (I) Y Aryl, das gegebenenfalls Substituenten aufweist, ist, oder ein pharmakologisch verträgliches Salz davon.
  3. Heterocyclische Amidverbindung gemäß Anspruch 1 oder Anspruch 2, wobei in der Formel (I) Z -CF2R8 oder -CF2CONR9R10 ist, oder ein pharmakologisch verträgliches Salz davon.
  4. Heterocyclische Amidverbindung gemäß einem der Ansprüche 1 bis 3, wobei in der Formel (I) eines von R5, R6 und R7 ein Aryl, das gegebenenfalls Substituenten aufweist, ist und die übrigen Wasserstoff sind, mit der Maßgabe, dass, wenn M Stickstoff ist, R6 nicht vorhanden ist, oder ein pharmakologisch verträgliches Salz davon.
  5. Verbindung der Formel (II)    wobei die Substituenten wie in Anspruch 1 definiert sind.
  6. Heterocyclische Amidverbindung 2-[5-Methylamino-2-(4-dimethylaminophenyl)-6-oxo-1,6-dihydro-1-pyrimidyl]-N-(1-benzyl-3,3,3-trifluor-2-oxopropyl)-acetamid oder ein pharmakologisch verträgliches Salz davon.
  7. Arzneimittel, umfassend die heterocyclische Amidverbindung gemäß einem der Ansprüche 1 bis 4 oder 6 oder ein pharmakologisch verträgliches Salz davon und einen pharmakologisch verträglichen Träger.
  8. Arzneimittel gemäß Anspruch 7, das ein Chymaseinhibitor ist.
EP96912273A 1995-04-27 1996-04-26 Heterocyclische amidverbindungen und deren medizinische verwendung Expired - Lifetime EP0826671B1 (de)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP10431495 1995-04-27
JP104314/95 1995-04-27
JP10431495 1995-04-27
PCT/JP1996/001171 WO1996033974A1 (en) 1995-04-27 1996-04-26 Heterocyclic amide compounds and medicinal use of the same

Publications (3)

Publication Number Publication Date
EP0826671A1 EP0826671A1 (de) 1998-03-04
EP0826671A4 EP0826671A4 (de) 1998-09-02
EP0826671B1 true EP0826671B1 (de) 2004-12-29

Family

ID=14377479

Family Applications (1)

Application Number Title Priority Date Filing Date
EP96912273A Expired - Lifetime EP0826671B1 (de) 1995-04-27 1996-04-26 Heterocyclische amidverbindungen und deren medizinische verwendung

Country Status (7)

Country Link
US (1) US5948785A (de)
EP (1) EP0826671B1 (de)
KR (1) KR100400639B1 (de)
CN (2) CN1188401C (de)
CA (1) CA2219364A1 (de)
DE (1) DE69634122D1 (de)
WO (1) WO1996033974A1 (de)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7960415B2 (en) 2003-05-27 2011-06-14 Vertex Pharmaceutical Incoporated Caspase inhibitors and uses thereof
US8362043B2 (en) 2004-11-24 2013-01-29 Vertex Pharmaceuticals Incorporated Caspase inhibitors and uses thereof

Families Citing this family (75)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20000068354A (ko) * 1996-09-06 2000-11-25 다께다 가즈히꼬 신규 아세트아미드 유도체 및 프로테아제 저해제
US6262047B1 (en) 1996-10-11 2001-07-17 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6369080B2 (en) * 1996-10-11 2002-04-09 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6063794A (en) 1996-10-11 2000-05-16 Cor Therapeutics Inc. Selective factor Xa inhibitors
US6194435B1 (en) 1996-10-11 2001-02-27 Cor Therapeutics, Inc. Lactams as selective factor Xa inhibitors
EP0940400A4 (de) * 1996-10-25 2002-10-02 Mitsubishi Pharma Corp Heterocyklische amidverbindungen und ihre medizinische anwendung
EP0971891A4 (de) * 1997-01-22 2000-04-19 Merck & Co Inc Thrombin-inhibitoren
NZ500354A (en) 1997-04-14 2001-11-30 Cor Therapeutics Inc Cyclic diaza compounds as selective factor Xa inhibitors for treating thrombotic related disorders
AU6896298A (en) 1997-04-14 1998-11-11 Cor Therapeutics, Inc. Selective factor xa inhibitors
US6369063B1 (en) 1997-04-14 2002-04-09 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6333321B1 (en) 1997-08-11 2001-12-25 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6228854B1 (en) 1997-08-11 2001-05-08 Cor Therapeutics, Inc. Selective factor Xa inhibitors
US6218382B1 (en) 1997-08-11 2001-04-17 Cor Therapeutics, Inc Selective factor Xa inhibitors
WO1999032459A1 (en) * 1997-12-22 1999-07-01 Yoshitomi Pharmaceutical Industries, Ltd. Chymase inhibitors
EP1055683A4 (de) * 1998-02-17 2007-07-25 Nippon Kayaku Kk Neuartiges acetamid-derivat und verwendung desselben
US6528514B1 (en) 1998-03-11 2003-03-04 Welfide Corporation IgE antibody production inhibitors and autoimmune diseases inhibitors
HUP0103256A3 (en) 1998-07-15 2002-05-28 Teijin Ltd Thiobenzimidazole derivatives and pharmaceutical compositions containing the compounds
US20050267148A1 (en) * 1998-07-15 2005-12-01 Teijin Limited Benzimidazole derivative
WO2000010605A2 (en) * 1998-08-20 2000-03-02 Senju Pharmaceutical Co., Ltd. Preventives or remedies for eye circulatory failure
BR0010758A (pt) * 1999-05-19 2003-06-10 Pharmacia Corp Aril e heteroaril pirimidinonas policìclicas substituìdas úteis como anti coagulantes
US6716838B1 (en) 1999-05-19 2004-04-06 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl uracils as anticoagulative agents
US6653316B1 (en) 1999-05-19 2003-11-25 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl pyrimidinones useful for selective inhibition of the coagulation cascade
US7015230B1 (en) 1999-05-19 2006-03-21 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl uracils useful for selective inhibition of the coagulation cascade
US6750342B1 (en) 1999-05-19 2004-06-15 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl pyrimidinones useful for selective inhibition of the coagulation cascade
US6867217B1 (en) 1999-05-19 2005-03-15 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl pyridones useful for selective inhibition of the coagulation cascade
US6664255B1 (en) 1999-05-19 2003-12-16 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl pyrazinones useful for selective inhibition of the coagulation cascade
US6458952B1 (en) 1999-05-19 2002-10-01 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl uracils useful for selective inhibition of the coagulation cascade
AU7447500A (en) * 1999-09-30 2001-04-30 Mitsubishi Chemical Corporation Acylsulfonamide derivatives
AU7954900A (en) * 1999-10-25 2001-05-08 Senju Pharmaceutical Co., Ltd. Tension-relieving agents for ciliary muscle
ATE360423T1 (de) * 1999-11-01 2007-05-15 Daiichi Asubio Pharma Co Ltd Verwendung von chymase hemmern gegen vaskuläre lipidablagerung
CN1245979C (zh) 2000-02-22 2006-03-22 第一阿斯比奥制药株式会社 含有胃促胰酶抑制剂作为有效成分的预防和治疗皮炎的药物
CN1366461A (zh) 2000-02-22 2002-08-28 三得利株式会社 含有胃促胰酶抑制剂作为有效成分的预防或治疗纤维变性的药物
EP1174151B1 (de) 2000-02-22 2007-01-24 Daiichi Asubio Pharma Co., Ltd. Therapeutische behandlung von eosinophilie durch verwendung von chymase-inhibitoren als aktiven bestandteilen
WO2001068605A1 (en) 2000-03-13 2001-09-20 Pharmacia Corporation Polycyclic aryl and heteroaryl substituted benzenes useful for selective inhibition of the coagulation cascade
CA2405306A1 (en) 2000-04-05 2001-10-18 Pharmacia Corporation Polycyclic aryl and heteroaryl substituted 4-pyridones useful for selective inhibition of the coagulation cascade
AU2001249870A1 (en) 2000-04-05 2001-10-23 Pharmacia Corporation Polycyclic aryl and heteroaryl substituted 4-pyrones useful for selective inhibition of the coagulation cascade
CA2405684A1 (en) 2000-04-17 2001-10-25 Pharmacia Corporation Polycyclic aryl and heteroaryl substituted 1,4-quinones useful for selective inhibition of the coagulation cascade
WO2001087851A1 (en) * 2000-05-18 2001-11-22 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl pyrimidinones useful for selective inhibition of the coagulation cascade
ES2320973T3 (es) * 2000-06-12 2009-06-01 EISAI R&D MANAGEMENT CO., LTD. Compuestos de 1,2-dihidropiridina, procedimiento para su preparacion y uso de los mismos.
CA2416248A1 (en) * 2000-07-18 2002-01-24 Neurogen Corporation 5-substituted 2-aryl-4-pyrimidinones
US7015223B1 (en) 2000-11-20 2006-03-21 Pharmacia Corporation Substituted polycyclic aryl and heteroaryl 1,2,4-triazinones useful for selective inhibition of the coagulation cascade
MXPA03004458A (es) 2000-11-20 2005-01-25 Pharmacia Corp Arilpiridinas y heteroarilpiridinas sustituidas utiles para inhibicion selectiva de la cascada de coagulacion.
US7119094B1 (en) 2000-11-20 2006-10-10 Warner-Lambert Company Substituted polycyclic aryl and heteroarpyl pyrazinones useful for selective inhibition of the coagulation cascade
JPWO2002051815A1 (ja) * 2000-12-26 2004-04-22 小野薬品工業株式会社 ピリミジン誘導体化合物およびそれらの製造方法
WO2003007964A1 (en) * 2001-07-18 2003-01-30 Nippon Kayaku Kabushiki Kaisha Remedial or preventive agent for cardiopathy or aneurysm containing chymase inhibitory compound
AU2002367752A1 (en) 2001-10-03 2003-11-17 Pharmacia Corporation Substituted 5-membered polycyclic compounds useful for selective inhibition of the coagulation cascade
EP1438292A1 (de) 2001-10-03 2004-07-21 Pharmacia Corporation 6-gliedrige heterocyclische verbindungen, die sich zur selektiven inhibierung der koagulationskaskade eignen
GB0129260D0 (en) 2001-12-06 2002-01-23 Eisai London Res Lab Ltd Pharmaceutical compositions and their uses
AU2003242270A1 (en) * 2002-06-14 2003-12-31 Ajinomoto Co., Inc. Process for producing pyrimidine compound
US20060148833A1 (en) * 2002-07-30 2006-07-06 Schroff Robert W Use of chymase inhibitors for the prevention and/or treatment of arterio-venous graft failure
KR20060120601A (ko) * 2003-08-22 2006-11-27 데이진 화-마 가부시키가이샤 키마제 저해제를 유효 성분으로서 함유하는 약제
EP1695967A1 (de) * 2003-11-04 2006-08-30 Ajinomoto Co., Inc. Verfahren zur herstellung von pyrimidinderivaten und zwischenprodukten
EP1533306A1 (de) * 2003-11-04 2005-05-25 Ajinomoto Co., Inc. Azlactone und Verfahren zu deren Herstellung
EP1529778A1 (de) * 2003-11-04 2005-05-11 Ajinomoto Co., Inc. Verfahren zu Herstellung von Pyrimidin- Derivat, Zwischenprodukt dafür
MY148809A (en) 2004-07-06 2013-05-31 Eisai R&D Man Co Ltd Crystals of 1,2-dihydropyridine compound and their production process
AR059898A1 (es) 2006-03-15 2008-05-07 Janssen Pharmaceutica Nv Derivados de 3-ciano-piridona 1,4-disustituida y su uso como moduladores alostericos de los receptores mglur2
TW200900065A (en) 2007-03-07 2009-01-01 Janssen Pharmaceutica Nv 3-cyano-4-(4-pyridinyloxy-phenyl)-pyridin-2-one derivatives
TW200845978A (en) 2007-03-07 2008-12-01 Janssen Pharmaceutica Nv 3-cyano-4-(4-tetrahydropyran-phenyl)-pyridin-2-one derivatives
SI2203439T1 (sl) 2007-09-14 2011-05-31 Ortho Mcneil Janssen Pharm 1',3'-disubstituirani 4-fenil-3,4,5,6-tetrahidro-2H-1'H-(1,4')bipiridinil-2'-oni
EP2344470B1 (de) 2008-09-02 2013-11-06 Janssen Pharmaceuticals, Inc. 3-azabicyclo[3.1.0]hexylderivate als modulatoren von metabotropen glutamatrezeptoren
JP5690277B2 (ja) 2008-11-28 2015-03-25 ジャンセン ファーマシューティカルズ， インコーポレイテッド． 代謝型グルタミン酸受容体の調節因子としてのインドールおよびベンゾオキサジン誘導体
US8501749B2 (en) 2009-01-30 2013-08-06 Boehringer Ingelheim International Gmbh Azaquinazolinediones chymase inhibitors
BRPI1010831A2 (pt) 2009-05-12 2016-04-05 Addex Pharmaceuticals Sa derivados de 1,2,4-triazolo[4,3-a]piridina e seu como moduladores alostéricos positivos de receptores de mglur2
MY153913A (en) 2009-05-12 2015-04-15 Janssen Pharmaceuticals Inc 7-aryl-1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mglur2 receptors
CN102439008B (zh) 2009-05-12 2015-04-29 杨森制药有限公司 1,2,4-三唑并[4,3-a]吡啶衍生物及其用于治疗或预防神经和精神病症的用途
KR101828094B1 (ko) * 2009-09-09 2018-03-22 이 아이 듀폰 디 네모아 앤드 캄파니 제초제 피리미돈 유도체
US9271967B2 (en) 2010-11-08 2016-03-01 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
ES2536433T3 (es) 2010-11-08 2015-05-25 Janssen Pharmaceuticals, Inc. Derivados de 1,2,4-triazolo[4,3-a]piridina y su uso como moduladores alostéricos positivos de receptores mGluR2
AU2011328203B2 (en) 2010-11-08 2015-03-19 Janssen Pharmaceuticals, Inc. 1,2,4-triazolo[4,3-a]pyridine derivatives and their use as positive allosteric modulators of mGluR2 receptors
JO3368B1 (ar) 2013-06-04 2019-03-13 Janssen Pharmaceutica Nv مركبات 6، 7- ثاني هيدرو بيرازولو [5،1-a] بيرازين- 4 (5 يد)- اون واستخدامها بصفة منظمات تفارغية سلبية لمستقبلات ميجلور 2
JO3367B1 (ar) 2013-09-06 2019-03-13 Janssen Pharmaceutica Nv مركبات 2،1، 4- ثلاثي زولو [3،4-a] بيريدين واستخدامها بصفة منظمات تفارغية موجبة لمستقبلات ميجلور 2
EP3066096A1 (de) * 2013-11-08 2016-09-14 Bayer Pharma Aktiengesellschaft Substituierte uracile als chymase inhibitoren
ME03518B (de) 2014-01-21 2020-04-20 Janssen Pharmaceutica Nv Kombinationen mit positiven allosterischen modulatoren von metabotropem glutamatergen rezeptor vom subtyp 2 und deren verwendung
MX386697B (es) 2014-01-21 2025-03-19 Janssen Pharmaceutica Nv Combinaciones que comprenden agonistas ortostericos o moduladores alostericos positivos del receptor glutamatergico metabotropico de subtipo 2 y su uso
WO2016039936A2 (en) * 2014-09-09 2016-03-17 Ptc Therapeutics, Inc. Monocyclic substituted 2-pyridinone antibacterial compounds

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9207145D0 (en) * 1991-04-18 1992-05-13 Ici Plc Heterocyclic amides
GB9216272D0 (en) * 1991-08-15 1992-09-09 Ici Plc Substituted heterocycles
US5441960A (en) * 1992-04-16 1995-08-15 Zeneca Limited 1-pyrimidinylacetamide human leukocyte elastate inhibitors
US5486529A (en) * 1992-04-16 1996-01-23 Zeneca Limited Certain pyridyl ketones for treating diseases involving leukocyte elastase
GB9307555D0 (en) * 1992-04-16 1993-06-02 Zeneca Ltd Heterocyclic compounds
CN1504462A (zh) * 1994-03-31 2004-06-16 ������˹ҩƷ��˾ 作为白细胞介素抑制剂的嘧啶基衍生物

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7960415B2 (en) 2003-05-27 2011-06-14 Vertex Pharmaceutical Incoporated Caspase inhibitors and uses thereof
US8362043B2 (en) 2004-11-24 2013-01-29 Vertex Pharmaceuticals Incorporated Caspase inhibitors and uses thereof

Also Published As

Publication number Publication date
US5948785A (en) 1999-09-07
CA2219364A1 (en) 1996-10-31
CN1188401C (zh) 2005-02-09
KR100400639B1 (ko) 2003-12-31
EP0826671A1 (de) 1998-03-04
EP0826671A4 (de) 1998-09-02
KR19990007998A (ko) 1999-01-25
CN1131210C (zh) 2003-12-17
CN1188472A (zh) 1998-07-22
DE69634122D1 (de) 2005-02-03
CN1304931A (zh) 2001-07-25
WO1996033974A1 (en) 1996-10-31

Similar Documents

Publication Publication Date Title
EP0826671B1 (de) Heterocyclische amidverbindungen und deren medizinische verwendung
EP0940400A1 (de) Heterocyklische amidverbindungen und ihre medizinische anwendung
EP1237878B1 (de) 4-pyrimidinyl-n-acyl-l-phenylanine
US6380387B1 (en) 4-Pyrimidinyl-n-acyl-l phenylalanines
AU725403B2 (en) Thrombin inhibitors
EP0761680A2 (de) Tetrazolverbindungen mit Interleukin-1beta-konvertierendes Enzym inhibierende Aktivität
EP1539696A2 (de) Verfahren zur herstellung antibiotischer chinolinzwischenprodukte
JP2008094842A (ja) ４−ピリジニル−ｎ−アシル−ｌ−フェニルアラニン
US20020119992A1 (en) Thrombin inhibitors
WO2008053913A1 (en) Sulfonylurea derivative capable of selectively inhibiting mmp-13
CA2853008A1 (en) Pharmaceutical compounds
HUT76648A (en) Difluorostatone, pharmaceutical compositions containing them and process for producing them
Bradbury et al. 1, 2, 4-Triazolo [4, 3-a] pyrazine derivatives with human renin inhibitory activity. 2. Synthesis, biological properties and molecular modeling of hydroxyethylene isostere derivatives
EP1737826A1 (de) Alpha-4-integrin-vermittelte zelladhäsionsinhibitoren zur behandlung bzw. prävention von entzündlichen erkrankungen
JPH107661A (ja) 新規複素環式アミド化合物およびその医薬用途
JPWO1999032459A1 (ja) キマーゼ阻害剤
WO1999032459A1 (en) Chymase inhibitors
JP3574455B2 (ja) 抗ウイルス剤として有用なマクロ環式ジフルオロスタトン誘導体類
EP1526131A1 (de) Aminoalkyl-Pyrazinone und -Pyridone verwendbar als Thrombininhibitoren
EP0717731B1 (de) Antivirale analoge von difluorostaton
CA2269720A1 (en) Novel heterocyclic amide compound and pharmaceutical use thereof
JPWO1996033974A1 (ja) 複素環式アミド化合物およびその医薬用途
KR0163671B1 (ko) N-아릴술포닐-알파-프로파길글리신아미드 유도체
JPH09136878A (ja) テトラゾール誘導体
JPWO1998018794A1 (ja) 新規な複素環式アミド化合物およびその医薬用途

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19971125

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): BE CH DE DK ES FR GB IT LI NL SE

RHK1 Main classification (correction)

Ipc: C07D239/46

A4 Supplementary search report drawn up and despatched

Effective date: 19980714

AK Designated contracting states

Kind code of ref document: A4

Designated state(s): BE CH DE DK ES FR GB IT LI NL SE

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: YOSHITOMI PHARMACEUTICAL INDUSTRIES, LTD.

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: WELFIDE CORPORATION

17Q First examination report despatched

Effective date: 20010518

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: MITSUBISHI PHARMA CORPORATION

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): BE CH DE DK ES FR GB IT LI NL SE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20041229

Ref country code: LI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20041229

Ref country code: IT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT;WARNING: LAPSES OF ITALIAN PATENTS WITH EFFECTIVE DATE BEFORE 2007 MAY HAVE OCCURRED AT ANY TIME BEFORE 2007. THE CORRECT EFFECTIVE DATE MAY BE DIFFERENT FROM THE ONE RECORDED.

Effective date: 20041229

Ref country code: FR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20041229

Ref country code: CH

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20041229

Ref country code: BE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20041229

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REF Corresponds to:

Ref document number: 69634122

Country of ref document: DE

Date of ref document: 20050203

Kind code of ref document: P

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20050329

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20050329

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20050330

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20050409

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20050426

NLV1 Nl: lapsed or annulled due to failure to fulfill the requirements of art. 29p and 29m of the patents act
REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20050930

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20050426

EN Fr: translation not filed